PHILADELPHIA – Six years ago, David C. Fajgenbaum, MD, MBA, MSc, both a Penn Medicine researcher and patient, tried an experimental treatment based on his laboratory research findings in the hopes of saving his own life. He has been in remission ever since. Now his further research is shedding new light on why it worked, paving the way for further testing of a new treatment approach in idiopathic multicentric Castleman disease (iMCD), a rare and deadly condition with limited options for patients. The work is led by Fajgenbaum, the director of the Center for Study & Treatment of Lymphadenopathies & Cytokine Storms (CSTL) in the Perelman School of Medicine at the University of Pennsylvania. Using 26 samples from iMCD patients, one of the largest research studies of this disease ever performed, Fajgenbaum and his team demonstrated that there is increased activation of a specific pathway called PI3K/Akt/mTOR. The findings suggest that patients who do not respond to the only drug currently approved by the U.S. Food and Drug Administration (FDA) for the treatment of the disease may have another option that targets this specific pathway. The research published this month in Blood.
Castleman disease isn’t actually a single disease. The term describes a group of inflammatory disorders that share a common appearance under the microscope. It’s diagnosed in about 5,000 people of all ages each year in the United States, which makes it roughly as common as Lou Gehrig’s disease, also called Amyotrophic Lateral Sclerosis or ALS. Patients experience a range of symptoms – from a single abnormal lymph node with mild flu-like symptoms to abnormal lymph nodes located throughout their entire body, abnormal blood cell counts, and life-threatening failure of multiple organ systems, such as the kidneys, liver, heart, and lungs.
The most severe subtype, iMCD, has similarities to both autoimmune conditions as well as cancer. About 35 percent of patients with iMCD will die within five years of diagnosis. In 2014, the FDA approved the drug siltuximab to treat iMCD, and studies have shown it can send between one-third and one-half of patients into a remission that generally lasts for years.
“Patients who don’t respond to siltuximab have limited options. They typically receive chemotherapy but often relapse,” said Fajgenbaum, who is also an assistant professor of Translational Medicine & Human Genetics at Penn and executive director of the Castleman Disease Collaborative Network (CDCN).
A med student, a former Division I quarterback, and a state-champion weight lifter, Fajgenbaum suddenly became sick in July 2010. In 2012, after failing to respond to other therapies and having relapsed multiple times after chemo, Fajgenbaum’s research on his own condition suggested that an inhibitor drug called sirolimus that blocked the PI3K/Akt/mTOR pathway could be effective. This drug is already available for the treatment of other conditions, particularly to prevent organ rejection after kidney transplantation. Based on his own research and in consultation with his treating physician, Fajgenbaum decided to test the drug on himself and has been in remission ever since. The results of testing the drug on himself and two additional patients were published in the Journal of Clinical Investigation last year.
“These expanded data clearly demonstrate that the PI3K/Akt /mTOR pathway is activated in iMCD. The next step is to test whether inhibition of the pathway is an effective treatment for a significant number of patients,” said Daniel Arenas, PhD, the study’s lead author and a medical student at Penn.
Fajgenbaum and his team are currently testing the treatment in a clinical trial (NCT03933904) ongoing at the University of Pennsylvania. Sunita Nasta, MD, FACP, an associate professor of Hematology-Oncology, and Adam Cohen, MD, an assistant professor of Hematology-Oncology, are enrolling and treating patients at Penn. The study is also enrolling patients at the University of Arkansas for Medical Sciences, led by Frits van Rhee, MD, PhD, the clinical director of the Myeloma Center.
Fajgenbaum also points out the larger implications this research has for the rare disease community.
“This highlights the potential for the approximately 1,500 drugs already approved for one condition to also be treatments or cures for the 7,000 diseases with no or insufficient treatment options like ALS and many pediatric cancers,” Fajgenbaum said.
This study was supported by the Castleman’s Awareness & Research Effort, the Penn Center for Precision Medicine, the University of Pennsylvania University Research Foundation, and the National Institutes of Health (R01-HL141408).